The extensive literature on the epidemiology of schizophrenia has provided decisive support for a major contribution of genetic factors to the aetiology of this disorder. Moreover, several recent lines of evidence reviewed in the main body of the CCNMD application have strongly implicated abnormal myelination as a pathogenic processes underlying schizophrenia. From the above, we postulate that DNA sequence variation within genes encoding proteins involved in myelination alter the structure or expression of these proteins. In this application, we will to test this hypothesis. We will screen genes involved in myelination for DNA sequence variation affecting protein sequence and expression. Genes will be selected based upon the gene expression, neuropathology and neuroimaging studies which form other strands of this center application. We will also screen perigenic and intronic sequences that have been identified by our CCNMD colleagues using bio-informatic approaches as potential regulatory elements. We will test whether the identified variants are involved in susceptibility to schizophrenia by looking for association between these variants and schizophrenia in a large ethnically homogeneous large case control association sample of 860 UK Caucasians meeting DSM-IV criteria for schizophrenia and 860 UK Caucasian blood donor controls. All variants showing evidence for significant association in the full case control sample (p <0.001) will be genotyped in 230 UK Caucasian parent-proband trios to ensure the findings are not attributable to stratification. Non-synonymous polymorphisms showing association will be examined for effects on gene expression by our colleagues in this CCNMD (Buxbaum/Project 2) who will look for correlation between genotype gene expression correlation in mRNA extracted from postmortem brains. Additionally, polymorphisms in proximal 5 ? flanking regulatory elements showing evidence for association with schizophrenia will be tested in a reporter gene assay in 3 mammalian cell lines for evidence that the associated variant alters gene expression. Currently, even using advanced bioinformatics, it is not possible to directly identify all DNA sequences involved in regulating gene expression since the location of all such sequences cannot be known for any gene. To ensure comprehensive analysis of our hypothesis, all genes with polymorphisms in genomic sequence corresponding to mRNA will be screened indirectly for polymorphisms altering gene expression by measuring the relative expression levels of the alleles within RNA samples from heterozygous. The research is dedicated to the longer term goal of understanding the mechanisms of schizophrenia and identifying genetically valid subtypes.